Effective alleviation of depressive and anxious symptoms and sleep disorders in benzodiazepine-dependent patients through repetitive transcranial magnetic stimulation.

Benzodiazepine (BZD) dependence poses a significant challenge in mental health, prompting the exploration of treatments like repetitive transcranial magnetic stimulation (rTMS). This research aims to assess the impact of rTMS on alleviating symptoms of BZD dependence. A randomized control trial was employed to study 40 BZD-dependent inpatients. Their symptoms were quantified using the Hamilton Anxiety Rating Scale (HAMA), Montgomery-Åsberg Depression Rating Scale (MADRS) and Pittsburgh Sleep Quality Index (PSQI). Participants were divided into a conventional treatment group (daily diazepam with gradual tapering) with supportive psychotherapy and another group receiving the same treatment supplemented with rTMS (five weekly sessions for 2 weeks). Significant improvements were observed in both groups over baseline in MADRS, HAMA and PSQI scores at the 2nd, 4th, 8th and 12th week assessments (p < 0.05). The group receiving rTMS in addition to conventional treatment exhibited superior improvements in all measures at the 8th and 12th weeks. The addition of rTMS to conventional treatment methods for BZD dependence significantly betters the recovery in terms of depression, anxiety and sleep quality, highlighting the role of rTMS as an effective adjunct therapy.

Drug dependence and prescribing ketamine for treatment-resistant depression in Australia and New Zealand.

Ketamine is a restricted and regulated medication in Australia and New Zealand, which has implications when considering treatment for patients with treatment-resistant depression and a history of illicit drug use, abuse or dependence. Regulations governing prescription of ketamine for treatment-resistant depression vary between jurisdictions in Australia and New Zealand, though most restrict use in those with drug dependence. There is substantial variation in definitions of drug dependence used in each jurisdiction, and between the legal and clinical definitions, with the latter specified in the current International Classification of Diseases, Eleventh Revision and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. This paper reviews the literature assessing the risk of ketamine misuse and dependence in patients with a history of illicit drug use, abuse or dependence and presents recommendations for psychiatrists who prescribe ketamine in such patients with treatment-resistant depression.

Effects of novel beta-lactam, MC-100093, and ceftriaxone on astrocytic glutamate transporters and neuroinflammatory factors in nucleus accumbens of C57BL/6 mice exposed to escalated doses of morphine.

Chronic exposure to opioids can lead to downregulation of astrocytic glutamate transporter 1 (GLT-1), which regulates the majority of glutamate uptake. Studies from our lab revealed that beta-lactam antibiotic, ceftriaxone, attenuated hydrocodone-induced downregulation of GLT-1 as well as cystine/glutamate antiporter (xCT) expression in central reward brain regions. In this study, we investigated the effects of escalating doses of morphine and tested the efficacy of novel synthetic non-antibiotic drug, MC-100093, and ceftriaxone in attenuating the effects of morphine exposure in the expression of GLT-1, xCT, and neuroinflammatory factors (IL-6 and TGF-ß) in the nucleus accumbens (NAc). This study also investigated the effects of morphine and beta-lactams in locomotor activity, spontaneous alternation percentage (SAP) and number of entries in Y maze since opioids have effects in locomotor sensitization. Mice were exposed to moderate dose of morphine (20 mg/kg, i.p.) on days 1, 3, 5, 7, and a higher dose of morphine (150 mg/kg, i.p.) on day 9, and these mice were then behaviorally tested and euthanized on Day 10. Western blot analysis showed that exposure to morphine downregulated GLT-1 and xCT expression in the NAc, and both MC-100093 and ceftriaxone attenuated these effects. In addition, morphine exposure increased IL-6 mRNA and TGF-ß mRNA expression, and MC-100093 and ceftriaxone attenuated only the effect on IL-6 mRNA expression in the NAc. Furthermore, morphine exposure induced an increase in distance travelled, and MC-100093 and ceftriaxone attenuated this effect. In addition, morphine exposure decreased the SAP and increased the number of arm entries in Y maze, however, neither MC-100093 nor ceftriaxone showed any attenuating effect. Our findings demonstrated for the first time that MC-100093 and ceftriaxone attenuated morphine-induced downregulation of GLT-1 and xCT expression, and morphine-induced increase in neuroinflammatory factor, IL-6, as well as hyperactivity. These findings revealed the beneficial therapeutic effects of MC-100093 and ceftriaxone against the effects of exposure to escalated doses of morphine.

The Concept of Resistance to Substance Use and a Research Approach: The Resist! Project.

Illicit substance use is dangerous in both acute and chronic forms, frequently resulting in lethal poisoning, addiction, and other negative consequences. Similar to research in other psychiatric conditions, whose ultimate goal is to enable effective prevention and treatment, studies in substance use are focused on factors elevating the risk for the disorder. The rapid growth of the substance use problem despite the effort invested in fighting it, however, suggests the need in changing the research approach. Instead of attempting to identify risk factors, whose neutralization is often infeasible if not impossible, it may be more promising to systematically reverse the perspective to the factors enhancing the aspect of liability to disorder that shares the same dimension but is opposite to risk, that is, resistance to substance use. Resistance factors, which enable the majority of the population to remain unaffected despite the ubiquity of psychoactive substances, may be more amenable to translation. While the resistance aspect of liability is symmetric to risk, the resistance approach requires substantial changes in sampling (high-resistance rather than high-risk) and using quantitative indices of liability. This article provides an overview and a practical approach to research in resistance to substance use/addiction, currently implemented in a NIH-funded project. The project benefits from unique opportunities afforded by the data originating from two longitudinal twin studies, the Virginia Twin Study of Adolescent and Behavioral Development and the Minnesota Twin Family Study. The methodology described is also applicable to other psychiatric disorders.

Escalating costs of self-injury mortality in the 21st century United States: an interstate observational study.

BACKGROUND: Estimating the economic costs of self-injury mortality (SIM) can inform health planning and clinical and public health interventions, serve as a basis for their evaluation, and provide the foundation for broadly disseminating evidence-based policies and practices. SIM is operationalized as a composite of all registered suicides at any age, and 80% of drug overdose (intoxication) deaths medicolegally classified as 'accidents,' and 90% of corresponding undetermined (intent) deaths in the age group 15 years and older. It is the long-term practice of the United States (US) Centers for Disease Control and Prevention (CDC) to subsume poisoning (drug and nondrug) deaths under the injury rubric. This study aimed to estimate magnitude and change in SIM and suicide costs in 2019 dollars for the United States (US), including the 50 states and the District of Columbia. METHODS: Cost estimates were generated from underlying cause-of-death data for 1999/2000 and 2018/2019 from the US Centers for Disease Control and Prevention's (CDC's) Wide-ranging ONline Data for Epidemiologic Research (WONDER). Estimation utilized the updated version of Medical and Work Loss Cost Estimation Methods for CDC's Web-based Injury Statistics Query and Reporting System (WISQARS). Exposures were medical expenditures, lost work productivity, and future quality of life loss. Main outcome measures were disaggregated, annual-averaged total and per capita costs of SIM and suicide for the nation and states in 1999/2000 and 2018/2019. RESULTS: 40,834 annual-averaged self-injury deaths in 1999/2000 and 101,325 in 2018/2019 were identified. Estimated national costs of SIM rose by 143% from $0.46 trillion to $1.12 trillion. Ratios of quality of life and work losses to medical spending in 2019 US dollars in 2018/2019 were 1,476 and 526, respectively, versus 1,419 and 526 in 1999/2000. Total national suicide costs increased 58%-from $318.6 billion to $502.7 billion. National per capita costs of SIM doubled from $1,638 to $3,413 over the observation period; costs of the suicide component rose from $1,137 to $1,534. States in the top quintile for per capita SIM, those whose cost increases exceeded 152%, concentrated in the Great Lakes, Southeast, Mideast and New England. States in the bottom quintile, those with per capita cost increases below 70%, were located in the Far West, Southwest, Plains, and Rocky Mountain regions. West Virginia exhibited the largest increase at 263% and Nevada the smallest at 22%. Percentage per capita cost increases for suicide were smaller than for SIM. Only the Far West, Southwest and Mideast were not represented in the top quintile, which comprised states with increases of 50% or greater. The bottom quintile comprised states with per capita suicide cost increases below 24%. Regions represented were the Far West, Southeast, Mideast and New England. North Dakota and Nevada occupied the extremes on the cost change continuum at 75% and - 1%, respectively. CONCLUSION: The scale and surge in the economic costs of SIM to society are large. Federal and state prevention and intervention programs should be financed with a clear understanding of the total costs-fiscal, social, and personal-incurred by deaths due to self-injurious behaviors.

Effects of Acute Exercise on Affect, Anxiety, and Self-Esteem in Poly-Substance Dependent Inpatients.

INTRODUCTION: Negative affect and anxiety frequently precede the onset of drug use in those with substance use disorder (SUD). Low self-esteem may increase the risk of relapse. We examined the short-term effects of exercise on affect, anxiety, and self-esteem in inpatients with poly-SUD. METHODS: This is a multicenter randomized control trial (RCT) with a crossover design. Thirty-eight inpatients (37.3 ± 6.4 years; 84% male) from three clinics participated in 45 min of soccer, circuit training, and control condition (psychoeducation) in a random order. Positive and negative affect (PANAS), state anxiety (single item), and self-esteem (Rosenberg SE-scale) were measured immediately before, immediately after, 1-h, 2-h, and 4-h post-exercise. Heart rate and ratings of perceived exertion were taken. Effects were assessed using linear mixed effects models. RESULTS: Compared to the control condition, there were significant post-exercise improvements in positive affect (ß = 2.99, CI = 0.39: 5.58), self-esteem (ß = 1.84, CI = 0.49: 3.20), and anxiety (ß = -0.69, CI = -1.34: -0.04) after circuit training (shown) and soccer. Effects persisted 4-h post-exercise. Reductions in negative affect were observed 2-h (circuit training: ß = -3.39, CI = -6.35: -1.51) and 4-h (soccer: ß = -3.71, CI = -6.03: -1.39) post-exercise, respectively. CONCLUSION: Moderately strenuous exercise undertaken in naturalistic settings may improve mental health symptoms in poly-SUD inpatients for up to 4-h post-exercise.

Long-term exercise at different intensities can reduce the inflammatory response in the brains of methamphetamine-treated mice.

Methamphetamine (METH) is a highly addictive psychoactive drug that is used worldwide. Various approaches have been used to address METH dependence, but many of them have little effect. Previous studies have shown that exercise on a treadmill could reduce METH dependence in mice, but the intensity and duration of exercise that was needed to be effective was unknown. This study investigated the effects of low- and medium-intensity treadmill exercise on methamphetamine reward in male mice via conditioned place preference (CPP) training, and the levels of the inflammatory factors IL-1ß, IL-6 and TNF-α in three brain regions (cerebral cortex, hippocampus and striatum) were determined. The results showed that long-term medium-intensity exercise reduced the effects of methamphetamine on inflammation markers in the brain and CPP scores. In addition, long-term medium-intensity exercise decreased IL-1ß concentrations in the cerebral cortex and hippocampus, reduced IL-6 concentrations in the striatum, and reduced TNF-α concentrations in the cerebral cortex, hippocampus, and striatum in methamphetamine-treated mice; low-intensity exercise was less effective. The results indicated that long-term medium-intensity exercise could reduce concentrations of methamphetamine-induced encephalitis factors in male mice, while low-intensity exercise was less effective in alleviating dependence and inflammatory responses. It is suggested that exercise intensity is an important factor affecting the dependence level and inflammatory responses in the brain in mice administered methamphetamine.

Opportunities to Enhance Linkage to Hepatitis C Care Among Hospitalized People With Recent Drug Dependence in New South Wales, Australia: A Population-based Linkage Study.

BACKGROUND: People who inject drugs are at greater risk of hepatitis C virus (HCV) infection and hospitalization, yet admissions are not utilized for HCV treatment initiation. We aimed to assess the extent to which people with HCV notification, including those with evidence of recent drug dependence, are hospitalized while eligible for direct-acting antiviral (DAA) therapy, and treatment uptake according to hospitalization in the DAA era. METHODS: We conducted a longitudinal, population-based cohort study of people living with HCV in the DAA era (March 2016-December 2018) through analysis of linked databases in New South Wales, Australia. Kaplan-Meier estimates were used to report HCV treatment uptake by frequency, length, and cause-specific hospitalization. RESULTS: Among 57 467 people, 14 938 (26%) had evidence of recent drug dependence, 50% (n = 7506) of whom were hospitalized while DAA eligible. Incidence of selected cause-specific hospitalization was highest for mental health-related (15.84 per 100 person-years [PY]), drug-related (15.20 per 100 PY), and injection-related infectious disease (9.15 per 100 PY) hospitalizations, and lowest for alcohol use disorder (4.58 per 100 PY) and liver-related (3.13 per 100 PY). In total, 65% (n = 4898) of those who were hospitalized had been admitted ≥2 times, and 46% (n = 3437) were hospitalized ≥7 days. By the end of 2018, DAA therapy was lowest for those hospitalized ≥2 times, for ≥7 days, and those whose first admission was for injection-related infectious disease, mental health disorders, and drug-related complications. CONCLUSIONS: Among people who have evidence of recent drug dependence, frequent hospitalization-particularly mental health, drug, and alcohol admissions-presents an opportunity for engagement in HCV care.

High hepatitis C treatment uptake among people with recent drug dependence in New South Wales, Australia.

BACKGROUND & AIMS: High HCV treatment uptake among people at most risk of transmission is essential to achieve elimination. We aimed to characterise subpopulations of people with HCV based on drug dependence, to estimate direct-acting antiviral (DAA) uptake in an unrestricted treatment era, and to evaluate factors associated with treatment uptake among people with recent drug dependence. METHODS: HCV notifications in New South Wales, Australia (1995-2017) were linked to opioid agonist therapy (OAT), hospitalisations, incarcerations, HIV notifications, deaths, and prescription databases. Drug dependence was defined as hospitalisation due to injectable drugs or receipt of OAT, with indicators in 2016-2018 considered recent. Records were weighted to account for spontaneous clearance. Logistic regression was used to analyse factors associated with treatment uptake among those with recent drug dependence. RESULTS: 57,467 people were estimated to have chronic HCV throughout the DAA era. Treatment uptake was highest among those with recent (47%), compared to those with distant (38%), and no (33%) drug dependence. Among those with recent drug dependence, treatment was more likely among those with HIV (adjusted odds ratio [aOR] 1.71; 95% CI 1.24-2.36), recent incarceration (aOR 1.10; 95% CI 1.01-1.19), and history of alcohol use disorder (aOR 1.22; 95% CI 1.13-1.31). Treatment was less likely among women (aOR 0.78; 95% CI 0.72-0.84), patients of Indigenous ethnicity (aOR 0.75; 95% CI 0.69-0.81), foreign-born individuals (aOR 0.86; 95% CI 0.78-0.96), those with outer-metropolitan notifications (aOR 0.90; 95% CI 0.82-0.98), HBV coinfection (aOR 0.69; 95% CI 0.59-0.80), and >1 recent hospitalisation (aOR: 0.91; 95% CI 0.84-0.98). CONCLUSIONS: These data provide evidence of high DAA uptake among people with recent drug dependence, including those who are incarcerated. Enhancing this encouraging initial uptake among high-risk populations will be essential to achieve HCV elimination. LAY SUMMARY: To facilitate HCV elimination, those at highest risk of infection and transmission are a treatment priority. This study shows the successes of Australia's universal provision of DAA therapy in reducing the barriers to treatment which have historically persisted among people who inject drugs. Despite higher DAA therapy uptake among those with recent drug dependence, gaps remain. Strategies which aim to reduce marginalisation and increase treatment uptake to ensure equitable HCV elimination must be advanced.

Clinical prediction of extra-medical use of prescription pain relievers from a representative United States sample.

Use of prescription opioids 'beyond the bounds' of medical guidance can lead to opioid dependence. Yet recent efforts to predict extra-medical use of prescription pain relievers (EMPPR) have relied on electronic medical or pharmacy records. Because peak incidence of EMPPR occurs during adolescence- a time of relative health- administrative data may be inadequate. In this study, with data from a United States (US) population sample, we develop and internally validate an EMPPR prediction model. We analyzed data from 234,593 individuals aged 12-to-17-years, as sampled by the US National Survey of Drug Use and Health, 2004-2018, an annual cross-sectional survey. We encoded 14 predictors with onset prior to EMPPR initiation, including age, sex, and facets of drug and psychiatric history. We ranked these predictors by clinical utility before sequentially adding each to a regularized logistic regression model. On held-out test data (n = 23,685), the model performs well with 14 predictors, with an area under the precision recall curve (AUPRC) is 0.155. The area under the receiver operator curve (AUC) is 0.819, exceeding a recent benchmark on this dataset. Results are robust to survey redesign that occurred in 2015, and are not moderated by past-year use of medical services. In conclusion, while selection of predictors is limited to those with known timing prior to initiation of EMPPR rather than any cross-sectional variable, this model discriminates well. Good classification occurs even with a small set of clinically available predictors- age, a history of depression and alcohol, cigarette, and cannabis use.

Impaired motor cortical plasticity associated with cannabis use disorder in young adults.

Maladaptive cortical plasticity has been described in individuals with heroin and methamphetamine addiction and may mediate other substance abuse disorders. It is unknown whether cannabis dependence in humans alters the capacity for induction of cortical plasticity. The aim of this study was to non-invasively investigate cortical plasticity with transcranial magnetic stimulation in young adults who meet DSM-5 criteria for cannabis use disorder (CUD). Thirty men (ages 20- 30) who used cannabis daily over the previous 6 months (15 diagnosed of CUD) and 15 demographically matched non-users were enrolled in this study. All participants underwent two sessions of theta burst stimulation (TBS) in which either continuous TBS (cTBS; 600 pulses, 80% active motor threshold) or intermittent TBS (iTBS; 2-s train of cTBS repeated every 10 s for a total of 190 s, 600 pulses) was applied over the primary motor cortex. The effects of these protocols were assessed by analysing the contralateral motor evoked potentials (MEPs). The relationships between cortical plasticity and problematic cannabis use, degree of dependence, and nicotine addiction were also investigated. Significant MEP inhibition after cTBS was observed in both cannabis users without CUD and non-users, while this inhibition was not seen in cannabis users with CUD. Strikingly, less motor cortical plasticity was observed in subjects with severe problematic cannabis use. No significant differences between users and non-users were found in the iTBS-induced cortical plasticity measures. Our study provides the first evidence of maladaptive cortical plasticity associated with cannabis use disorder and problematic cannabis use in humans.

Explaining the Differences in Opioid Overdose Deaths between Scotland and England/Wales: Implications for European Opioid Policies.

BACKGROUNDS: Between 2009 and 2018, the number of opioid-related deaths (ORDs) in Scotland showed a dramatic increase, whereas in England and Wales, a much lower increase in ORD was seen. This regional difference is remarkable, and the situation in Scotland is worrisome. Therefore, it is important to identify the drivers of ORD in Scotland. METHODS: A systematic literature review according to PRISMA guidelines was conducted to identify peer-reviewed studies about key drivers for the observed differences in ORDs between Scotland and England/Wales. In addition, non-peer-reviewed reports on nationwide statistical data were retrieved via Google and Google Scholar and analysed to quantify differences in ORD drivers between Scotland and England/Wales. RESULTS: The systematic review identified some important drivers of ORD, but none of these studies provided direct or indirect comparisons of ORD drivers in Scotland and England/Wales. However, the reports with nationwide statistical data showed important differences in ORD drivers between Scotland and England/Wales, including a higher prevalence of people using opioids in a problematic way (PUOP), more polydrug use in people using drugs in a problematic way (PUDP), a higher age of PUDP, and lower treatment coverage and efficacy of PUDP in Scotland compared to England/Wales, but no regional differences in injecting drug use, incarceration/prison release without treatment, and social deprivation in PUDP. CONCLUSION: It is concluded that the opioid crisis in Scotland is best explained by a combination of drivers, consisting of a higher population involvement in (problematic) opioid use (notably methadone), relatively more polydrug use (notably benzodiazepines and gabapentinoids), a steeper ageing of the PUOP population in the past 2 decades, and lower treatment coverage and efficacy in Scotland compared to England/Wales. The findings have important consequences for strategies to handle the opioid crisis in Scotland.

Nonclinical evaluation of abuse liability of the dual orexin receptor antagonist lemborexant.

Lemborexant is a dual orexin receptor antagonist (DORA) approved in multiple countries including the United States, Japan, Canada and Australia for the treatment of adults with insomnia. As required for marketing approval of new compounds with central nervous system activity with sedating effects, the abuse potential of lemborexant was assessed in accordance with regulatory guidelines, which included three nonclinical studies. These assessments comprised physical dependence and drug discrimination studies in rats and a self-administration study in rhesus monkeys. There was no evidence of withdrawal signs following abrupt drug discontinuation, indicating that lemborexant does not induce physical dependence. In the drug discrimination study, lemborexant at doses up to 1000 mg/kg administered orally did not cross-generalize to the zolpidem training stimulus, although another DORA included in the same experiment, suvorexant, showed partial generalization with zolpidem. In rhesus monkeys, lemborexant treatment did not induce any gross behavioral changes, and there was no increase in self-administration rates compared with control, indicative of a lack of reinforcing effects of lemborexant. Collectively, these nonclinical studies support the position that lemborexant, which has been placed in Schedule IV by the United States Drug Enforcement Administration, has a low risk of abuse in humans.

Plants with Anti-Addictive Potential.

Drug addiction is prevalent among individuals of modern society, being a major cause of disability and premature loss of life. Although the drug addiction have profound social, economical and health impact in the world population, its management remains a challenge as available pharmacological treatments remains ineffective for most people. The limited efficacy and adverse effects have led to a search for alternative therapies to treat drug addiction. In this context, natural products are an important source for new chemical substances with a potential therapeutic applicability. Therefore, this chapter will present data obtained after an extensive literature search regarding the use of medicinal plants as a pharmacological alternative for drug addiction treatment.

[Research Progress on the Effect of Synthetic Cathinones on Animal Behavior].

ABSTRACT: Synthetic cathinones are a class of new psychoactive substances with a structure similar to amphetamine drugs, which can produce excitatory effects similar to drugs such as amphetamine and cocaine after being taken. In recent years, the abuse of synthetic cathinones worldwide has become increasingly serious, posing a serious threat to social security and public health. This article focuses on several common synthetic cathinones, collects their research results in animal autonomous activity experiments and drug dependence model experiments and summarizes their relevant experimental conclusions in animal body temperature regulation, learning and memory, and anxiety, in order to provide data reference and method guidance for the domestic development of related drug research.

Network failures: When incentives trigger impulsive responses.

Adequate control of impulsive urges to act is demanded in everyday life but is impaired in neuropsychiatric conditions such as stimulant use disorder. Despite intensive research it remains unclear whether failures in impulse control are caused by impaired suppression of behavior or by the over invigoration of behavior by stimuli associated with salient incentives such as drugs, food, and money. We investigated failures in impulse control using functional magnetic resonance imaging (fMRI) to map the neural correlates of premature (impulsive) responses during the anticipation phase of the Monetary Incentive Delay (MID) task in healthy controls (HC), stimulant-dependent individuals (SDIs), and their unaffected first-degree siblings (SIB). We combined task-based fMRI analyses with dynamic causal modeling to show that failures of impulse control were associated with interactions between cingulo-opercular and dorsal striatal networks regardless of group status and incentive type. We further report that group-specific incentive salience plays a critical role in modulating impulsivity in SDIs since drug-related incentives specifically increased premature responding and shifted task modulation away from the dorsal striatal network to the cingulo-opercular network. Our findings thus indicate that impulsive actions are elicited by salient personally-relevant incentive stimuli and those such slips of action recruit a distinct fronto-striatal network.

Forecasting Opioid Use Disorder at 25 Years of Age in 16-Year-Old Adolescents.

OBJECTIVE: To evaluate the accuracy of detecting 16-year-old male (n = 465) and female (n = 162) youths who subsequently manifest opioid use disorder (OUD) at 25 years of age. We hypothesized that the combined measures of 2 components of etiology, heritable risk, and substance use, accurately detect youths who develop OUD. STUDY DESIGN: Heritable risk was measured by the transmissible liability index (TLI). Severity of the prodrome presaging OUD was quantified by the revised Drug Use Screening Inventory containing the consumption frequency index (CFI) documenting substance use events during the past month and the overall problem density (OPD) score indicating co-occurring biopsychosocial problems. Diagnosis of OUD was formulated by a clinical committee based on results of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition in conjunction with medical and social history records. RESULTS: Bivariate analysis shows that the TLI, CFI, and OPD scores at 16 years of age predict OUD at 25 years. Multivariate modeling indicates that the TLI combined with the CFI predict OUD with 86% accuracy (sensitivity = 87%; specificity = 62%). The TLI and CFI at 16 years of age mediate the association between parental substance use disorder and OUD in offspring at 25 years of age, indicating that these measures respectively evaluate risk and prodrome. CONCLUSIONS: These results demonstrate the feasibility of identifying youths requiring intervention to prevent OUD.

Excitability, synaptic balance, and addiction: The homeostatic dynamics of ionotropic glutamatergic receptors in VTA after cocaine exposure.

Glutamatergic AMPA and NMDA receptors in the ventral tegmental area (VTA) are central for cocaine first exposure and posterior craving maintenance. However, the exact rules that coordinate the synaptic dynamics of these receptors in dopaminergic VTA neurons and behavioral outcomes are poorly understood. Additionally, synaptic homeostatic plasticity is present in response to chronic excitability changes in neuronal circuits, adjusting the strength of synapses to stabilize the firing rate. Despite having correspondent mechanisms, little is known about the relationship between continuous cocaine exposure and homeostatic synaptic changes in the VTA neurons. Here, we assess the role of homeostatic mechanisms in the neurobiology of cocaine addiction by providing a brief overview of the parallels between cocaine-induced synaptic potentiation and long-term synaptic adaptations, focusing on the regulation of GluA1- and GluN1- containing receptors.

United States vs Safehouse: The implications of the Philadelphia supervised consumption facility ruling for law and social stigma.

In October 2019, a federal judge ruled that a Philadelphia nonprofit (Safehouse) group's plan to open the first site in the U.S. where people can use illegal opioids under medical supervision does not violate federal Controlled Substances Act, delivering a major setback to Justice Department lawyers who launched a legal challenge to block the facility. The Judge wrote that "the ultimate goal of Safehouse's proposed operation is to reduce drug use, not facilitate it," which represents the first legal decision about whether supervised injection sites can be legally permissible under U.S. law. Although supervised consumption facilities ("SCFs") remain controversial, they already exist in many countries in Europe as well as Canada, Australia, and Mexico, and evaluations of their public health impact have demonstrated the value of this practice. The decision is hailed as a public health victory and could shape the legal debate in other U.S. cities. Challenges remain as stigmatizing attitudes regarding substance use are widely accepted, culturally endorsed, and enshrined in policy. The Safehouse case shows that SCFs might be able to survive under current federal drug laws, but public understanding and support of these facilities will also be crucial for cities and states to open them.

The Streetlight Effect: Reappraising the Study of Addiction in Light of the Findings of Genome-wide Association Studies.

Drug dependence has long been thought to have a genetic component. Research seeking to identify the genetic basis of addiction has gone through important transitions over its history, in part based upon the emergence of new technologies, but also as the result of changing perspectives. Early research approaches were largely dictated by available technology, with technological advancements having highly transformative effects on genetic research, but the limitations of technology also affected modes of thinking about the genetic causes of disease. This review explores these transitions in thinking about the genetic causes of addiction in terms of the "streetlight effect," which is a type of observational bias whereby people search for something only where it is easiest to search. In this way, the genes that were initially studied in the field of addiction genetics were chosen because they were the most "obvious," and formed current understanding of the biological mechanisms underlying the actions of drugs of abuse and drug dependence. The problem with this emphasis is that prior to the genomic era the vast majority of genes and proteins had yet to be identified, much less studied. This review considers how these initial choices, as well as subsequent choices that were also driven by technological limitations, shaped the study of the genetic basis of drug dependence. While genome-wide approaches overcame the initial biases regarding which genes to choose to study inherent in candidate gene studies and other approaches, genome-wide approaches necessitated other assumptions. These included additive genetic causation and limited allelic heterogeneity, which both appear to be incorrect. Thus, the next stage of advancement in this field must overcome these shortcomings through approaches that allow the examination of complex interactive effects, both gene × gene and gene × environment interactions. Techniques for these sorts of studies have recently been developed and represent the next step in our understanding of the genetic basis of drug dependence.